Patients with autoimmunity make too much of certain antibodies, especially those directed to "self". Our crude current therapies for these conditions could be greatly improved if we only understood and could manipulate the early events in B lymphocyte activation well enough to turn down specific immune responses to restore self-tolerance. Major accomplishments of cellular immunology in the last decade have been to understand how the antibody response is regulated by a variety of growth and differentiation factors (lymphokines) from T cells and macrophages, and to define several different mechanisms of tolerance. One of those mechanisms is intrinsic tolerance in B cells to attack this problem systematically. We have selected six such events, including significant early, intermediate and late events: 1) membrane depolarization (within 1 hr); 2) increase in cell volume (in less than 1 day); 3) increase in cell surface Ia expression (at about 1 day); 4) accelerated shedding of surface Ig; 5) accelerated replacement of surface IgM and IgG from day 1 to day 4; and 6) progress through the cell cycle to S phase on day 3 to 4. We will show whether these events can be elicited in purified antigen-binding cells from tolerant and nontolerant animals by the following forms of "signal 1": anti-Mu, anti-Gamma, LPS, dextran sulfate, and thymus-independent and dependent antigen. Then we will show how the performance of these early events is affected by the addition of a "second signal" in the form of interleukin 1, B cell growth factors 1 or 2, two T replacing factors from different T cell lines, and interferon. Thus our research has the dual purpose of revealing the impact of lymphokines and intrinsic tolerance on the physiology of the responding B cell.